Serotonin and Cognition General Insights

Serotonin (5-hydroxytryptamine, or 5-HT) is involved in multiple cerebral functions including learning, memory, mood, anxiety, and impulsiveness (Aouizerate et al. 2005; Coccaro 1989; Cools et al. 2008). Serotonin acts through multiple receptors that are classified as 5-HTj to 5-HT7, each one showing subclasses, based on their affinity to agonists and based on their cellular signaling pathways (Roth 1994). 5-HT2 receptors are all coupled to Gq protein and are members of the rhodopsin family of G-protein-coupled receptors (Aghajanian and Marek 1997). Their activation results in stimulation of phospholipase C and the production of inositol phosphate (Conn and Sanders-Bush 1986). 5-HT2 receptors are located in 5-HT terminal regions and are particularly dense in deeper cortical layers, including the prefrontal and anterior cin-gulated cortices, and in the hippocampus and the thalamus, all of which are brain regions known to be involved in learning (Fischette et al. 1987; Pazos et al. 1987).

Subclasses of 5-HT2 receptors include 5-HT2A, 5-HT2B, and 5-HT2C; the latter exhibits the unique mechanism of generating multiple functional receptor variants through messenger ribonucleic acid (mRNA) editing (Burns et al. 1997).

5-HT2C mRNA is restricted almost exclusively to the central nervous system (Julius et al. 1988), where it is distributed in areas including the cerebral cortex, limbic system, and basal ganglia (Rick et al. 1995; Sheldon and Aghajanian 1991). 5-HT2C receptors have a widespread distribution in humans, monkeys, and rats and exist both pre- and postsynaptically (Lopez-Gimenez et al. 2001). In the monkey

Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social and

División de Estudios de Posgrado, Facultad de Ciencias Médicas y Biológicas "Dr. Ignacio

Chávez", Universidad Michoacana de San Nicolás de Hidalgo and

Instituto de Física y Matemáticas de física y matemáticas, Universidad Michoacana de San Nicolás de Hidalgo e-mail: [email protected]; [email protected]

G.Di Giovanni et al. (eds.), 5-HT2C Receptors in the Pathophysiology of CNS Disease, 461

The Receptors 22, DOI 10.1007/978-1-60761-941-3_24, © Springer Science + Business Media, LLC 2011

brain, 5-HT2C receptors show an extensive and heterogeneous distribution, with the strongest concentration in the choroid plexus (Lopez-Gimenez et al. 2001). In the neocortex, 5-HT2C receptor mRNA has been detected in layer V of all cortical regions except in the calcarine sulcus. The striatum and basal forebrain show strong staining for the receptor mRNA (autoradiographic study) in the nucleus accumbens, ventral aspects of caudate-putamen (striatum), septal nuclei, Broca diagonal band, ventral striatum, and amygdale, as well as in several thalamic, midbrain, and brain-stem nuclei. The location of receptors is primarily somatodendritic, possibly, on axon terminals in several regions including septal nuclei and the horizontal limb of the diagonal band and the interpeduncular nucleus (presence of mRNA without binding sites). Especially abundant 5-HT2C mRNA has been found in some regions with a high population of cholinergic cells (Lopez-Gimenez et al. 2001). In the rat, high levels of 5-HT2C receptors have been observed in the prefrontal cortex (Pompeiano et al. 1994), mainly located on the apical dendrites of pyramidal neurons and less on parvalbumin-labeled yaminobutyric acid (GABA) interneurons (Miner et al. 2003). A widespread distribution of 5-HT2C mRNA has also been found in the rat. Clemett (Clemett et al. 2000) observed the most abundant mRNA content in the neuronal bodies in the anterior olfactory nucleus, medial and intercalated amygdaloid nuclei, hippocampus subfields CA1 to CA3, laterodorsal and lateral geniculated thalamic nuclei, caudate-putamen, and several cortical areas, including piriform and frontal. The 5-HT2C receptors are present in the CA1 sub-field of the rat hippocampus at all developmental stages (Garcia-Alcocer et al. 2006). Immunopositive neurons are also located in the dorsal raphe, where a role as autoreceptors has been proposed (Clemett et al. 2000).

The presence of 5-HT2C receptors in the cell bodies or terminal regions of the three dopaminergic systems (Alex and Pehek 2007) suggests that this receptor is a modulator of dopaminergic system functioning and of the learning processes in which dopamine neurotransmission is involved. An indirect inhibition of tonic dopamine release by 5-HT2C receptors through the activation of GABA-ergic cells and the consequent increase in GABA release occurs in either the substantia nigra pars reticulata or the striatum (nigrostriatal pathway). The 5-HT2C receptors appear to tonically inhibit the release of dopamine in the cortical targets of the mesocorti-cal pathway, but this effect does not appear to be exerted at the cortical level but at the ventral tegmental area (Alex and Pehek 2007; Di Matteo et al. 2001).

In the ventral tegmental area, 5-HT2C receptors are located on subpopulations of both GABA-ergic and dopaminergic neurons, its density (of 5-HT2C receptors) showing higher levels in the middle region and a lower expression in more caudal regions (Bubar and Cunningham 2007; Ji et al. 2006), whereas in the striatum and nucleus accumbens, 5-HT2C receptors are only located on GABA-ergic neurons (Eberle-Wang et al. 1997).

Thus, in view of the presence of 5-HT2C receptors on dopaminergic neurons, it is possible that these receptors exert a modulatory effect on learning involving the cerebral areas that are targets of the dopaminergic system, in which the dopamine exerts a principal role in organizing learning processes, as is the case in the prefron-tal cortex and striatum.

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